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tolerated and did not induce hypoxaemia in 12 weeks. However, there was a trend towards a decrease of forced vital capacity and diffusing capacity of the lung for carbon monoxide, while 6-min walking distance (6MWD) decreased from 320.9 m (232.96–408.84 m) to 302.9 m (205.01–400.79 m); p,0.05. Bosentan was not superior over the placebo in 6MWD in another double-blind, multicentre trial which included 158 patients with idiopathic pulmonary fibrosis [3]. Since the use of bosentan among patients with parenchymal lung disease has not proved to be favourable, the hypothesis that it could be beneficial for COPD subjects because they establish elevated levels of endothelin is rather weak. While selective pulmonary vasodilation may benefit chronic obstructive pulmonary disease patients with increased pulmonary artery pressure during stress [4], this study was not designed to prove such an effect of bosentan. The pathophysiology of exercise limitation in severe chronic obstructive pulmonary disease subjects and the ventilation/perfusion ratio mismatching, which is induced by unselective pulmonary vasodilation [5], should have been taken more seriously under consideration in the study design of STOLZ et al. [1]. A.K. Boutou, I. Stanopoulos, G. Pitsiou and P. Argyropoulou Respiratory Failure Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece. STATEMENT OF INTEREST None declared. REFERENCES 1 Stolz D, Rasch H, Linka A, et al. A randomised, controlled trial of bosentan in severe COPD. Eur Respir J 2008; 32: 619–628. 2 Gunther A, Enke B, Markart P, et al. Safety and tolerability of bosentan in idiopathic pulmonary fibrosis: an open label study. Eur Respir J 2007; 29: 713–719. 3 King TE Jr, Behr J, Brown KK, et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008; 177: 75–81. 4 Stanopoulos I, Manolakoglou N, Pitsiou G, et al. Sildenafil may facilitate weaning in mechanically ventilated COPD patients: a report of three cases. Anaesth Intensive Care 2007; 35: 610–613. 5 Agusti AG, Barbera JA, Roca J, Wagner PD, Guitart R, Rodriguez-Roisin R. Hypoxic pulmonary vasoconstriction and gas exchange during exercise in chronic obstructive pulmonary disease. Chest 1990; 97: 268–275. DOI: 10.1183/09031936.00146108 To the Editors: We read with interest the study by STOLZ et al. [1] reporting on the lack of improvement of exercise capacity caused by the dual endothelin-1 antagonist bosentan in patients with severe chronic obstructive pulmonary disease (COPD) and absence of severe pulmonary hypertension (PH) at rest. Pulmonary vasodilators, 450 VOLUME 33 NUMBER 2 like bosentan or sildenafil, may not work in patients with COPD-related PH, a condition dominated by right ventricular diastolic dysfunction with normal cardiac output [2]. However, STOLZ et al. [1] acknowledged that these results may not apply to uncommon cases of severe PH associated with COPD. Thus it was suggested that PH-specific treatment first be studied in the subgroup of patients identified by CHAOUAT et al. [3], with severe disproportionate PH [4, 5], arbitrarily defined by a mean pulmonary arterial pressure (P̄pa) of .40 mmHg [3]. Herein, we report dramatic functional improvement with bosentan therapy in a patient with COPD and severe disproportionate PH. A 53-yr-old female with a history of obesity (body mass index 41 kg?m-2), type II diabetes, hypothyroidism and acute pulmonary embolism 3 yrs previously, was followed for severe COPD. She was a former smoker (30 pack-yrs) and her dyspnoea was functional class III. After two episodes of right cardiac failure 3 yrs previously she was receiving furosemide 80 mg?day-1. Obstructive sleep apnoea syndrome was ruled out. High-resolution computed tomography of the chest showed mild diffuse emphysema. Pulmonary function tests showed severe airflow obstruction with air trapping and hyperinflation: forced vital capacity (FVC) 2.3 L (76% predicted), total lung capacity 6.3 L (128% pred), forced expiratory volume in one second (FEV1) 0.84 L (34% pred), FEV1/FVC 37%, residual volume 4.0 L (226% pred) and carbon monoxide diffusion capacity was 87% pred. The patient had been on long-term oxygen therapy (2.5 L?min-1) for 3 yrs, with arterial oxygen tension (Pa,O2) on long-term oxygen therapy of 11.0 kPa, but elevated carbon dioxide arterial tension (Pa,CO2; table 1). PH suggested by echocardiography was confirmed by right heart catheterisation, demonstrating a pulmonary artery pressure of 110/50 mmHg (mean 65 mmHg), with a transpulmonary gradient of 49 mmHg, cardiac index of 2.6 L?min-1?m-2 and pulmonary vascular resistance (PVR) of 739 dyn?s?cm-5 without response to inhaled NO. No chronic thromboembolic disease or other cause of PH was found. The patient had not taken anorexigens and left ventricular function was normal. Since the contribution of PH to exercise limitation was considered significant and dyspnoea gradually increased, therapy with oral bosentan was initiated at 62.5 mg b.i.d. for 4 weeks, then increased to 125 mg b.i.d. Oral anticoagulation was initiated and long-term oxygen therapy was kept unchanged. Within 4 weeks of bosentan initiation, dyspnoea significantly decreased to functional class II. The patient was able to resume activities such as home cleaning, going shopping and going to the beach. She could climb one flight of stairs without stopping (as opposed to no more than 5–10 steps before treatment) and resumed indoor biking. However, arterial blood gas analysis showed increased Pa,CO2 (9.6 kPa), and nocturnal noninvasive nasal ventilation was initiated 1 yr after the diagnosis of PH. Clinical improvement persisted throughout follow-up. Bosentan was well tolerated. The 6-min walk test distance had improved from 198 to 360 m 2 yrs after initiating bosentan therapy. Right heart cavities EUROPEAN RESPIRATORY JOURNAL TABLE 1 Patient characteristics and outcome with bosentan Time frame Diagnosis of PH 6 months 12 months 18 months 24 months Oxygen therapy L?min-1 2.5 2.5 2.5 2.5 2.5 Noninvasive ventilation No No Started Yes Yes WHO functional class III I/II II II II 6-min walk distance m 198 306 294 294 360 Echocardiographic data Estimated sPAP mmHg Right cavities 110 60 Severe dilatation, Undilated Undilated Undilated RV/LV size ratio 1.8 Right heart catheterisation P̄pa mmHg 65 dPAP – Ppw mmHg 34 34 7 CI L?min-1?m-2 2.6 3.7 PVR dyn?s?cm-5 739 214 Pulmonary function tests FVC % pred 76 75 66 69 81 FEV1 % pred 34 27 29 28 39 11.6 Pa,O2 with 2.5 L?min-1 O2 kPa 11.0 9.1 10.7 10.7 Pa,CO2 kPa 7.9 9.6 7.8 7.0 7.2 pH 7.39 7.37 7.37 7.38 7.40 PH: pulmonary hypertension; WHO: World Health Organization; sPAP: systolic pulmonary artery pressure; P̄pa: mean pulmonary artery pressure; dPAP: diastolic pulmonary artery pressure; Ppw: pulmonary artery wedge pressure; CI: cardiac index; PVR: pulmonary vascular resistance; FVC: forced vital capacity; % pred: % predicted; FEV1: forced expiratory volume in one second; Pa,O2: arterial oxygen tension; Pa,CO2: arterial carbon dioxide tension; RV: right ventricular; LV: left ventricular. were no longer dilated at echocardiography, and right heart catheterisation showed that PVR decreased to 214 dyn?s?cm-5, cardiac index increased to 3.7 L?min-1?m-2 and P̄pa was 34 mmHg. Pulmonary function tests were unchanged (table 1). Improvement of PH was not explained by weight loss [6], or by changes in Pa,O2. Interestingly, in the study by STOLZ et al. [1], bosentan therapy was associated with a significant decrease in Pa,O2, presumably related to increased ventilation–perfusion mismatching, intrapulmonary right-to-left microshunting (itself due to quantitative perfusion augmentation or fluid retention) and/or the reduction of peripheral carotid body sensitivity with a decrease in hypoxic ventilatory response. Indeed, Pa,CO2 was further increased in our patient while on bosentan, leading to the initiation of noninvasive ventilation. pneumologie – centre de référence des maladies pulmonaires rares, Lyon, and ePolyclinique, Sallanches, France. 1Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. STATEMENT OF INTEREST Statements of interest for V. Cottin, R. Lazor and J-F. Cordier can be found at www.erj.ersjournals.com/misc/statements.shtml V. Cottin*,#,",+, C. Khouatra*,", R. Lazor*,",1, P. Canue and J-F. Cordier*,#,",+ *Hospices Civils de Lyon, #Université de Lyon, Université Lyon I, + UCBL-INRA-ENVL-EPHE, UMR754 IFR128, Université Lyon I, and "Hôpital Louis Pradel, Service de REFERENCES 1 Stolz D, Rasch H, Linka A, et al. A randomised, controlled trial of bosentan in severe COPD. Eur Respir J 2008; 32: 619–628. 2 Hoeper MM. Treating pulmonary hypertension in COPD: where do we start? Eur Respir J 2008; 32: 541–542. 3 Chaouat A, Bugnet AS, Kadaoui N, et al. Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005; 172: 189–194. 4 Thabut G, Dauriat G, Stern JB, et al. Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation. Chest 2005; 127: 1531–1536. 5 Weitzenblum E, Delcroix M. Treatment of pulmonary hypertension in chronic obstructive pulmonary disease. In: Siafakas N, ed. Management of Chronic Obstructive Pulmonary Disease. Eur Respir Mon 2006; 38: 313–324. EUROPEAN RESPIRATORY JOURNAL VOLUME 33 NUMBER 2 This observation suggests that clinical trials are warranted to evaluate the possible efficacy of pulmonary hypertensionspecific therapy in patients with chronic obstructive pulmonary disease and disproportionate pulmonary hypertension and characterise possible responders [3–5]. However, detrimental effects on gas exchange should be carefully monitored. 451 c 6 Mathier MA, Zhang J, Ramanathan RC. Dramatic functional improvement following bariatric surgery in a patient with pulmonary arterial hypertension and morbid obesity. Chest 2008; 133: 789–792. DOI: 10.1183/09031936.00161808 From the authors: We are pleased by the great interest in our recently published manuscript [1]. In their letter, V. Cottin and co-workers describe the clinical course of a patient with chronic obstructive pulmonary disease (COPD) Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III and disproportional pulmonary hypertension, who showed considerable benefit from oral bosentan. The authors noted an improvement in 6-min walking test distance of .160 m 2 yrs after initiating bosentan therapy, but also reported a marked increase in carbon dioxide arterial tension levels. Indeed, the case report of V. Cottin and colleagues seems to illustrate the fact that patients with COPD and disproportional pulmonary hypertension could well improve on selective pulmonary vasodilators, despite disadvantageous effects on gas exchange. Nevertheless, with regard to the case report of V. Cottin and colleagues, we believe that the contribution of bilevel positive airway pressure (BiPAP) therapy for possible alveolar hypoventilation (body mass index 41 kg?m2) and residual previous pulmonary embolism might need to be considered in the context of clinical improvement. A further argument supporting the hypothesis that pulmonary hypertension in V. Cottin and colleagues’ case report was not solely related to COPD, was the fact that no major abnormalities were evidenced by computed tomography scan and diffusion capacity was well preserved, uncommon findings in advanced emphysema. Moreover, haemodynamics in pulmonary arterial hypertension usually improve only marginally in most patients treated with pulmonary vasodilators, even when their clinical response to therapy is excellent [2]. In contrast, pulmonary hypertension in patients with adipositas hypoventilation syndrome is largely reversible on BiPAP ventilation, a feature also observed in this case (mean pulmonary artery pressure decreased from 65 mmHg to 34 mmHg under ventilation). We fully agree with V. Cottin and colleagues that randomised, controlled trials are the only reliable way to evaluate the efficacy of a drug with regard to a particular patient population. The comments of C. Jardim and R. Souza merely summarise the limitations of our randomised, double-blind, placebocontrolled study, which have already been extensively mentioned in the original manuscript [1]. It should be noted that a similar study [3], in which right heart catheterisation at rest and during exercise was performed, also failed to show an improvement in stroke volume or exercise capacity following a 3-month treatment period with sildenafil. The absence of a treatment response was independent of the presence of pulmonary hypertension [3]. C. Jardim and R. Souza also ask for subgroup analyses. However, it is well known that 452 VOLUME 33 NUMBER 2 investigators need to exercise caution when drawing conclusions from subgroup analyses as they have a proclivity to detect spurious effects [4]. We are not aware of a pathophysiological denominator between COPD-related pulmonary hypertension and hepatosplenic schistosomiasis, as cited in the letter by C. Jardim and R. Souza. It is well known that pulmonary hypertension considerably aggravates during exercise in patients with severe COPD. Until now it has been unclear to what extent pulmonary hypertension limits exercise tolerance in severe COPD, given that pulmonary hypertension and the resulting right ventricular dysfunction could account for both muscle fatigue and hypoxia. Therefore, considering the patient profile of COPD and the general efficacy and established ease of use of oral endothelin (ET)-1 antagonists in patients with pulmonary arterial hypertension, it would be appropriate to consider whether the use of ET-1 receptor antagonist may find a valuable place in the therapy of pulmonary hypertension associated with COPD [5]. There are several similarities between patients with COPD and those with primary pulmonary hypertension: fibromuscular intimal thickening with a diffuse increase in smooth muscle cells within the intima [6]; low bronchoalveolar levels of vascular endothelial growth factor [7]; activation of phospholipase A2 [8]; and both epithelial and endothelial increased cell proliferation [9]. It is important to note that increased lipid peroxidation is a feature of all forms of pulmonary hypertension, including that seen in COPD [10], and endothelial nitric oxide production is decreased in COPD [11]. There is also evidence that ETA and ETB receptor expression is increased in the pulmonary arteries of patients with COPD [12], contrasting with heart failure in which the ET receptor expression is reduced [13] where ET-1 antagonists fail to affect the disease. Thus, although ET-1 levels do not correlate with survival in patients with COPD [14], and in contrast to the statements by A.K. Boutou and co-workers, there are strong pathobiological associations between the pulmonary vascular changes of COPD and ET-1 [5]. Moreover, prior to this trial, the efficacy of newer pulmonary vasodilators in patients with COPD was described in one case series, which showed a beneficial effect of pulmonary vasodilator therapy [15]. It is worth noting that the latter was an open label study rather than a placebo-controlled trial [15]. A.K. Boutou and colleagues also argue that bosentan has not proved to be favourable in patients with interstitial lung disease and therefore the hypothesis that it could be beneficial in patients with COPD is ‘‘rather weak’’. However, the study cited by A.K. Boutou and co-workers explicitly excluded patients with pulmonary arterial hypertension [16]. We might also add that the pathophysiology of COPD and idiopathic pulmonary fibrosis differs. In summary, at the current time, there is evidence suggesting that patients with pulmonary hypertension due to severe chronic obstructive pulmonary disease will not benefit from pulmonary vasodilator therapy as evidence by our study [1] and by the study of RIETEMA et al. [3]. Whether patients suffering from ‘‘disproportional’’ pulmonary hypertension and chronic obstructive pulmonary disease might benefit from therapy remains to be proved in a randomised, placebocontrolled trial addressing this question. EUROPEAN RESPIRATORY JOURNAL